Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells

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• 作者：Mercedes Bermejo^a ; ¹ ; Marí ; a Rosa Ló ; pez-Huertas^a ; ¹ ; Javier Garcí ; a-Pé ; rez^a ; Nú ; ria Climent^b ; Benjamin Descours^c ; Juan Ambrosioni^d ; Elena Mateos^a ; Sara Rodrí ; guez-Mora^a ; Lucí ; a Rus-Bercial^a ; Monsef Benkirane^c ; José ; M. Miró ; ^d ; Montserrat Plana^b ; José ; Alcamí ; ^a ; Mayte Coiras^a ; ^{mcoiras@isciii.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HIV-1 reservoir ; Dasatinib ; SAMHD1 ; CD4+ T lymphocytes ; Chronic myeloid leukemia
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：106
• 期：Complete
• 页码：30-45
• 全文大小：2578 K

文摘

Massive activation of infected CD4+ T cells during acute HIV-1 infection leads to reservoir seeding and T-cell destruction. During T-cell activation, the antiviral effect of the innate factor SAMHD1 is neutralized through phosphorylation at T592, allowing HIV-1 infection. Dasatinib, a tyrosine kinase inhibitor currently used for treating chronic myeloid leukemia, has been described to control HIV-1 replication through its negative effect on T-cell proliferation and viral entry. We demonstrate that Dasatinib can actually interfere with SAMHD1 phosphorylation in human peripheral blood lymphocytes, preserving its antiviral activity against HIV-1. Dasatinib prevented SAMHD1 phosphorylation in vitro and ex vivo, impairing HIV-1 reverse transcription and proviral integration. This was the major mechanism of action because the presence of Vpx, which degrades SAMHD1, in HIV-1 virions impeded the inhibitory effect of Dasatinib on HIV-1 replication. In fact, infection with VSV-pseudotyped HIV-1 virions and fusion of BlaM-Vpr-containing HIV-1 viruses with activated PBMCs in the presence of Dasatinib suggested that Dasatinib was not acting at fusion level. Finally, PBMCs from patients on chronic treatment with Dasatinib showed a lower level of SAMHD1 phosphorylation in response to activating stimuli and low susceptibility to HIV-1 infection ex vivo. Consequently, Dasatinib is a compound currently used in clinic that preserves the antiviral function of SAMHD1. Using Dasatinib as adjuvant of antiretroviral therapy during early primary HIV-1 infection would contribute to reduce viral replication and spread, prevent reservoir seeding, and preserve CD4 counts and CTL responses. These events would create a more favorable virologic and immunologic environment for future interventional studies aiming at HIV-1 eradication.